First clear evidence of a link between SARS-CoV-2 infection and Kawasaki disease

Detailed analysis from the epicentre of the Italian COVID-19 outbreak describes increase in cases of rare Kawasaki-like disease in young children, adding to reports of similar cases from New York, USA and South East England, UK. Syndrome is rare and experts stress that children remain minimally affected by SARS-CoV-2 infection overall.

Doctors in the Bergamo province of Italy have described a series of ten cases of young children with symptoms similar to a rare inflammatory disease called Kawasaki Disease appearing since the COVID-19 pandemic arose in the Lombardy region of Northern Italy, in a report published today in The Lancet.

Only 19 children had been diagnosed with the condition in that area in the five years up to the middle of February 2020, but there were 10 cases between 18 February and 20 April 2020. The latest reports could represent a 30-fold increase in the number of cases, although researchers caution that it is difficult to draw firm conclusions with such small numbers.

Eight of the 10 children brought to hospital after 18 February 2020 tested positive for the SARS-coronavirus-2 virus (SARS-CoV-2) in an antibody test. All of the children in the study survived, but those who became ill during the pandemic displayed more serious symptoms than those diagnosed in the previous five years.

Kawasaki Disease is a rare condition that typically affects children under the age of five. It causes blood vessels to become inflamed and swollen. The typical symptoms include fever and rash, red eyes, dry or cracked lips or mouth, redness on the palms of the hands and soles of the feet, and swollen glands.

Typically, around a quarter of children affected experience cardiac complications, but the condition is rarely fatal if treated appropriately in hospital. It is not known what triggers the condition but it is thought to be an abnormal immune overreaction to an infection.

Dr. Lucio Verdoni, author of the report from the Hospital Papa Giovanni XXIII in Bergamo, Italy, said: “We noticed an increase in the number of children being referred to our hospital with an inflammatory condition similar to Kawasaki Disease around the time the SARS-CoV-2 outbreak was taking hold in our region.

Although this complication remains very rare, our study provides further evidence on how the virus may be affecting children.

Parents should follow local medical advice and seek medical attention immediately if their child is unwell. Most children will make a complete recovery if they receive appropriate hospital care.”

The study authors carried out a retrospective review of patient notes from all 29 children admitted to their paediatric unit with symptoms of Kawasaki Disease from 1 January 2015 to 20 April 2020.

Before the COVID-19 outbreak, the hospital treated around one case of Kawasaki Disease every three months. Between 18 February and 20 April 2020, 10 children were treated for symptoms of the disease.

The increase could not be explained by an increase in hospital admissions, as the number of patients admitted during that time period was six fold lower than before the virus was first reported in the area.

Children who presented at hospital with symptoms after 18 February 2020 were older on average (mean age 7.5 years) than the group diagnosed in the previous five years (mean age 3 years).

They also appeared to experience more severe symptoms than past cases, with more than half (60%, 6/10 cases) having heart complications, compared with just 10% of those treated before the pandemic (2/19 cases).

Half of the children (5/10) had signs of toxic shock syndrome, whereas none of the children treated before February 2020 had this complication. All patients before and after the pandemic received immunoglobulin treatment, but 80% of children during the outbreak (8/10) required additional treatment with steroids, compared with 16% of those in the historical group (4/19).

Two of the patients treated after 18 February 2020 (2/10) tested negative for SARS-CoV-2 on an antibody test. The researchers say the test used is not 100% accurate (95% sensitivity and 85-90% specificity), suggesting these could be false negative results.

In addition, one of the patients had recently been treated with a high dose of immunoglobulin, a standard treatment for Kawasaki Disease, which could have masked any antibodies to the virus.

Taken together, the authors say that their findings represent an association between an outbreak of SARS-CoV-2 virus and an inflammatory condition similar to Kawasaki Disease in the Bergamo province of Italy.

The researchers say the COVID-related cases should be classified as ‘Kawasaki-like Disease’, as the symptoms were different and more severe in patients treated after March 2020.

However, they caution that their report is based on only a small number of cases and larger studies will be required to confirm the association. They also warn that other countries affected by the COVID-19 pandemic might expect to see a similar rise in cases similar to Kawasaki Disease.

Dr. Lorenzo D’Antiga, lead author of the study from the Hospital Papa Giovanni XXIII in Bergamo, Italy, said:

“We are starting to see case reports of children presenting at hospital with signs of Kawasaki Disease in other areas hit hard by the COVID-19 pandemic, including New York and South East England [3, 4].

Our study provides the first clear evidence of a link between SARS-CoV-2 infection and this inflammatory condition, and we hope it will help doctors around the world as we try to get to grips with this unknown virus.”

Dr. Annalisa Gervasoni, another author of the study and a Paediatric Specialist at the Hospital Papa Giovanni XXIII in Bergamo, Italy, said: “In our experience, only a very small proportion of children infected with SARS-CoV-2 develop symptoms of Kawasaki Disease.

However, it is important to understand the consequences of the virus in children, particularly as countries around the world grapple with plans to start relaxing social distancing policies.”

Writing in a linked Comment, Professor Russell Viner, President of the Royal College of Paediatrics and Child Health and Professor of Adolescent Health, UCL Great Ormond Street Institute of Child Health, UK, (who was not involved in the study), said: “Although the Article suggests a possible emerging inflammatory syndrome associated with COVID-19, it is crucial to reiterate – for parents and health-care workers alike – that children remain minimally affected by SARS-CoV-2 infection overall.

Understanding this inflammatory phenomenon in children might provide vital information about immune responses to SARS-CoV-2 and possible correlates of immune protection that might have relevance both for adults and children.

In particular, if this is an antibody-mediated phenomenon, there might be implications for vaccine studies, and might also explain why some children become very ill with COVID-19, while the majority are unaffected or asymptomatic.”

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In December 2019, a series of pneumonia cases of unknown cause emerged in Wuhan, Hubei, China, with clinical presentations greatly resembling viral pneumonia.¹ Deep sequencing analysis from lower respiratory tract samples indicated a novel coronavirus, which was named Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2).

As of April 14^th 2020, a total of 1,844,863 cases of SARS-CoV-2 infection and 117,021 deaths have been confirmed by the World Health Organization.² The most feared clinical presentation of Coronavirus disease 2019 (COVID-19) is bilateral interstitial pneumonia, which may progress to acute respiratory distress syndrome (ARDS). The latter occurs in approximately 3-30% of hospitalized patients with COVID-19, depending on the cohort.^1,3–8

Analyzing the first reports from China, a considerable proportion of patients (12-28%) presented elevated cardiac troponin levels.^1,6,8,9 Compared with patients with normal levels, those with elevated troponins were older and had significantly higher rates of comorbidities including hypertension, coronary artery disease (CAD) and diabetes.⁶ Notably, patients with higher troponin levels were more likely to be admitted to intensive care^1,5 and showed higher in-hospital mortality.^{6–8,10–13}

Acute respiratory infections as well as sepsis are often associated with a troponin rise, which can be used as a marker of disease severity and predicts future cardiovascular events.^14–16 Hypotheses on COVID-19-associated myocardial injury are consistent with previous observations relating to the outbreaks of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). Several mechanisms have been proposed, which are summarized in Figure 1 . In the following paragraphs we provide an overview of the available evidence regarding the possible mechanisms of myocardial injury in COVID-19.

Myocarditis

Myocarditis is defined as an inflammatory disease of the myocardium diagnosed by established histological, immunological and immunohistochemical criteria.17 Many viruses are cardiotropic, meaning they bind directly on molecular targets in the myocardium. Myocardial damage may be due to different mechanisms.

In the initial phase of viral myocarditis, direct virus-mediated lysis of cardiomyocytes occurs.18

This is usually followed by a robust T-cell response that can lead to further heart injury and ventricular dysfunction. 19,20 In COVID-19, particular attention has been given to the role of Angiotensin Converting Enzyme 2 (ACE2), the binding receptor for SARS-CoV-2 cellular entry.21

ACE2 is highly expressed in pericytes of adult human hearts, which indicates an intrinsic susceptibility of heart to SARS-CoV-2 infection.22 SARS-CoV-2 appears to not only gain initial entry through ACE2 but also to subsequently downregulate ACE2 expression, resulting in reduced conversion of Angiotensin II (Ang-II) to Angiotensin 1-7 (Ang-1-7). The latter physiologically mediates protective cardiovascular effects in target organs.23,24

In autopsies of patients who died from the SARS outbreak in 2002, 35% of heart samples showed the presence of viral RNA in the myocardium, which in turn was associated with reduced ACE2 protein expression.25

SARS-CoV-2 may share the same mechanism with the first SARS-coronavirus because the two viruses are highly homologous in genome.6,26,27 The consequences of ACE2 downregulation on the cardiovascular system is further expanded upon below.

Myocarditis represents one of the most challenging diagnoses in cardiology. Suspicion rises with the number of criteria fulfilled.17 However, diagnostic certainty is based on endomyocardial biopsy or autopsy, where histological analyses (infiltration, lymphocytes, macrophages, cellular inflammatory types) or molecular methods of viral genome identification can be performed.

To the best of our knowledge, only three case reports of probable COVID-19 myocarditis are available to date,28–30 but none have been proven by biopsy. A fourth case describes the autopsy of a patient with severe COVID-19 who died from sudden cardiac arrest.31 Interestingly, there were no obvious histological changes seen in heart tissue.

The emergency setting of many hospital facilities during the pandemic together with strict hygienic measures intended to prevent further contagion may hinder large studies on biopsy specimens in patients with COVID-19 and the performance of autopsies. At present, no convincing evidence of histologically confirmed COVID-19 myocarditis has been published.

Microangiopathy

SARS-CoV-2 uses ACE2 as its entry receptor, and subsequently downregulates ACE2 expression. In addition to the heart and lung, ACE2 is localized in the intestinal epithelium, vascular endothelium, and the kidneys.32,33 In the renin-angiotensin-aldosterone system, ACE2 catalyzes the conversion of Ang-II to Ang-1–7, which opposes the vasoconstrictor, pro-inflammatory, pro-oxidant, pro-proliferative and pro-fibrotic actions exerted by Ang-II via AT1 receptors.34

As a result, suppression of ACE2 expression and subsequent increase in Ang-II35 levels may represent another threat to heart and vessels in patients with COVID-19. However, the role of Ang-II/Ang-1-7 imbalance in COVID-19 is extrapolated based on limited data from a different, albeit closely related, coronavirus (SARS-CoV).

The clinical significance of this pathway in COVID-19 complications and any possible role of modulating this receptor are not yet fully known. A clinical trial testing recombinant human ACE2 as a treatment for patients with COVID-19 is currently ongoing (NCT04335136).

This drug may play a double role, both by acting as a decoy and competitively reducing viral cell entry, and by restoring ACE2 activity and its beneficial role.36

Endothelial dysfunction, cytokine storm, oxidative stress, and Ang-II upregulation may explain the coagulopathy frequently seen in severe coronavirus disease.37 A postmortem study from Singapore38 on patients with SARS reported that 4 patients out of 8 had pulmonary thromboembolic lesions and 3 patients had deep vein thrombosis.

To date, there is only one described case of COVID-19-associated pulmonary embolism,39 but around half of patients with COVID-19 present high levels of D-dimer,3 which is associated to disease severity and higher mortality.40

This marked elevation in D-dimer may be due to intense inflammation stimulating intrinsic fibrinolysis in the lungs with spillover into the bloodstream.41

Another factor that may contribute to microangiopathy is vasculitis. Several studies have linked coronavirus infection with Kawasaki disease, especially in children.42–44

Furthermore, a case series of three deceased SARS patients in 2003 described findings of systemic vasculitis, including edema, localized fibrinoid necrosis, and infiltration of monocytes, lymphocytes, and plasma cells into vessel walls in the heart, lung, liver, kidney, adrenal gland, and the stroma of striated muscles.45

It has been suggested that, in patients with COVID-19, microvascular damage occurring in the heart causes perfusion defects, vessel hyperpermeability and vasospasm, leading to myocardial injury.46,47

Notably, a considerable proportion of critically ill patients with COVID-19 present with acute kidney injury (AKI), which is associated with worse prognosis.8,48 The mechanism may be the same, with microangiopathy of renal vessels, but there is no strong supporting evidence to date. Worsening of troponin clearance in patients with AKI could also contribute to the elevated levels in those patients.

Myocardial infarction

Patients with pre-existing CAD and those with risk factors for atherosclerotic CVD are at an increased risk of developing an acute coronary syndrome (ACS) during acute infections, as demonstrated previously in epidemiologic and clinical studies of influenza49–51 and other acute inflammatory conditions.52

This could result from imbalance between oxygen supply and demand in the acute setting, so that the troponin elevation may be interpreted as a type 2 myocardial infarction (MI).53 Reduced oxygen supply in patients with COVID-19 is typically caused by hypoxic respiratory failure, a feature that is more common in deceased patients than in patients who recover10 and is a marker of disease severity.9

On the other hand, infectious states are often accompanied by fever, tachycardia and endocrine dysregulation, which lead to a marked increase in myocardial oxygen demand. Moreover, hypoxemia also leads to excessive intracellular calcium with consequent cardiac myocyte apoptosis.47

By definition, a type 2 MI can occur with or without underlying CAD. However, considering the higher prevalence of elevated troponin in patients with COVID-19 with previous CVD, it is possible that the type 2 MI when underlying stable coronary disease is unmasked by the acute infection.

Type 1 MI, caused by plaque rupture with thrombus formation, may also be precipitated by COVID-19.53 Circulating cytokines released during a severe systemic inflammatory stress could lead to atherosclerotic plaque instability and rupture.54

In addition, the suppression of ACE2 expression and Ang-II increase may elevate cardiovascular risk through mechanisms such as oxidative stress, endothelial dysfunction and vasoconstriction. Moreover, as ACE2 is expressed in vascular endothelial cells,32,33 direct viral vascular infection leading to plaque instability may also play a role in type 1 MI in patients with COVID-19.

The occurrence of ACS and MI in infected patients during the first SARS outbreak has been described.38,55 However, there are very scarce data about symptoms and ECG changes related to MI in COVID-19.

Chest pain has been broadly reported and is also associated with cardiac injury,7 but it has a very low specificity due to the primary lung disease (i.e. pleuritic pain). Interestingly, Guo et al. reported that on admission no patients showed evidence of acute myocardial infarction.6 No data regarding ECG changes on larger groups have been published to date.

Cytokine storm

Severe lung inflammation and impaired pulmonary gas exchange in COVID-19 has been suggested to be due to upregulation of pro-inflammatory cytokines.56 In healthy subjects, Ang-1-7 limits the synthesis of pro-inflammatory and pro-fibrotic cytokines.

Thus, downregulation of ACE2 by SARS-CoV-2, with a consequent reduction in Ang-1-7 levels, may magnify the cytokine storm resulting in an overwhelming inflammatory response.6,57

Cytokines have been extensively studied in patients with heart failure due to their role in inflammatory modulation, myocyte stress/stretch, myocyte injury and apoptosis, fibroblast activation and extracellular matrix remodeling.58

In the study by Guo et al., plasma troponin levels had a significant positive linear correlation with plasma high-sensitivity C-reactive protein levels, indicating that myocardial injury may be closely associated with inflammatory pathogenesis during the progress of disease.6

In addition to their direct effects on cardiomyocytes, high levels of circulating cytokines also lead to functional reprogramming of endothelial cells, endothelial dysfunction, and atherogenesis.6,59,60 In fact, endothelial cells are thought to play a primary role in the inflammatory response in viral infections.61

Thus, systemic inflammatory response with cytokine storm is a plausible cause of myocardial injury in the late phases of disease, usually associated with ARDS, multi-organ failure and mortality. Overall, high cytokine levels may represent the key player of myocardial injury in COVID-19, being related to direct myocardial injury, endothelial dysfunction, destabilization of coronary plaque, and microthrombogenesis.

Future perspectives

Troponin represents a useful marker of disease progression and prognosis in COVID-19. As noted by Guo et al.,6 the 16% of their patients with underlying CVD but normal troponin levels had a relatively favorable outcome. Therefore, myocardial biomarkers should be evaluated in patients with CVD who develop COVID-19 for risk stratification purposes to potentially lead to earlier and more aggressive interventions.

Numerous therapies have been proposed worldwide in order to reduce COVID-19 associated morbidity and mortality. Some are antiviral drugs acting directly on SARS-CoV-2, with conflicting results to date.62

Other ongoing trials are testing immunomodulating agents, aimed at reducing the excessive inflammatory response that characterizes severe disease progression. As evidence of inflammatory cell infiltration has been reported in the alveoli of patients with ARDS associated with SARS-CoV-2 infection,31 this could justify the use of corticosteroids in patients with COVID-19.

Another therapeutic possibility is drugs or biologics that act on the cytokine storm, especially targeting interleukin-163 and interleukin-6.64 Further observations on myocardial enzyme curves and imaging studies in patients treated with those drugs are needed to correlate immunomodulation with myocardial protection in COVID-19.

Another important issue in this disease is prevention of thrombotic complications. As noted, severe COVID-19 has been associated with high levels of D-dimer as a marker of a general prothrombotic state.37

Based on the immuno-thrombosis model, which highlights a bidirectional relationship between the immune system and thrombin generation, blocking thrombin by heparin may dampen the inflammatory response.65

Furthermore, heparin also has an anti-inflammatory function, which may be relevant in this setting.66 Several publications have demonstrated this property and some of the described mechanisms include binding to inflammatory cytokines, inhibition of neutrophil chemotaxis and leukocyte migration, neutralization of the positively charged peptide complement factor C5a, and sequestration of acute phase proteins.67–70A systematic review concluded that in the clinical setting, heparin can decrease the level of inflammatory biomarkers but stressed the need for more data from larger studies.71

Conclusion

Elevated troponin levels are frequent in patients with COVID-19 and significantly associated with fatal outcomes. Several mechanisms may explain this phenomenon: viral myocarditis, cytokine-driven myocardial damage, microangiopathy, and unmasked CAD.

At present, none of these mechanisms have been definitely proven to be the main driver of troponin elevation and/or myocardial damage in patients with COVID-19. However, we posit that, although COVID-19 initially presents as a primarily respiratory condition, it quickly involves the cardiovascular system through an imbalance of the renin-angiotensin-aldosterone system mediated by ACE2 depletion. This mechanism may complicate the clinical course mediated through the inflammatory response, endothelial dysfunction and microvascular damage.

Additional study of these mechanisms is clearly needed and may influence the search for ways to prevent myocardial damage (e.g. immunomodulating drugs). Given the impact of myocardial damage in the pathophysiology and prognosis of patients with COVID-19, the inclusion of cardiovascular endpoints in ongoing drug trials is essential.

It is reasonable to triage patients with COVID-19 according to the presence of underlying CVD and evidence of myocardial injury for prioritized treatment and even more aggressive treatment strategies in an effort to reduce mortality.

Conflict of interest: all authors have no conflict of interest to disclose.

References

1. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. The Lancet 2020; 395: 497–506.
2. World Health Organization. Coronavirus disease 2019 (COVID-19) Situation Report – 85.
3. Guan W, Ni Z, Hu Y, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med 2020; NEJMoa2002032.
4. Chen N, Zhou M, Dong X, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. The Lancet 2020; 395: 507–513.
5. Wang D, Hu B, Hu C, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected Pneumonia in Wuhan, China. JAMA 2020; 323: 1061.
6. Guo T, Fan Y, Chen M, et al. Cardiovascular Implications of Fatal Outcomes of Patients With Coronavirus Disease 2019 (COVID-19). JAMA Cardiol. Epub ahead of print 27 March 2020. DOI: 10.1001/jamacardio.2020.1017.
7. Shi S, Qin M, Shen B, et al. Association of Cardiac Injury With Mortality in Hospitalized Patients With COVID-19 in Wuhan, China. JAMA Cardiol. Epub ahead of print 25 March 2020. DOI: 10.1001/jamacardio.2020.0950.
8. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. The Lancet 2020; 395: 1054–1062.
9. Yang X, Yu Y, Xu J, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med 2020; S2213260020300795.
10. Chen T, Wu D, Chen H, et al. Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study. BMJ 2020; m1091.
11. Ruan Q, Yang K, Wang W, et al. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. Epub ahead of print 3 March 2020. DOI: 10.1007/s00134-020-05991-x.
12. He XW, Lai JS, Cheng J, et al. [Impact of complicated myocardial injury on the clinical outcome of severe or critically ill COVID-19 patients]. Zhonghua Xin Xue Guan Bing Za Zhi 2020; 48: E011.
13. Wang L, He W, Yu X, et al. Coronavirus Disease 2019 in elderly patients: characteristics and prognostic factors based on 4-week follow-up. J Infect 2020; S0163445320301468.
14. Long B, Long DA, Tannenbaum L, et al. An emergency medicine approach to troponin elevation due to causes other than occlusion myocardial infarction. Am J Emerg Med. Epub ahead of print 9 December 2019. DOI: 10.1016/j.ajem.2019.12.007.
15. Frencken JF, van Baal L, Kappen TH, et al. Myocardial Injury in Critically Ill Patients with Community-acquired Pneumonia. A Cohort Study. Ann Am Thorac Soc 2019; 16: 606–612.
16. Menéndez R, Méndez R, Aldás I, et al. Community-Acquired Pneumonia Patients at Risk for Early and Long-term Cardiovascular Events Are Identified by Cardiac Biomarkers. Chest 2019; 156: 1080–1091.
17. Caforio ALP, Pankuweit S, Arbustini E, et al. Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J 2013; 34: 2636–2648, 2648a–2648d.
18. Maekawa Y, Ouzounian M, Opavsky MA, et al. Connecting the missing link between dilated cardiomyopathy and viral myocarditis: virus, cytoskeleton, and innate immunity. Circulation 2007; 115: 5–8.
19. Lawson CM. Evidence for mimicry by viral antigens in animal models of autoimmune disease including myocarditis. Cell Mol Life Sci CMLS 2000; 57: 552–560.
20. Badorff C, Knowlton KU. Dystrophin disruption in enterovirus-induced myocarditis and dilated cardiomyopathy: from bench to bedside. Med Microbiol Immunol (Berl) 2004; 193: 121–126.
21. Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. Epub ahead of print 4 March 2020. DOI: 10.1016/j.cell.2020.02.052.
22. Chen L, Li X, Chen M, et al. The ACE2 expression in human heart indicates new potential mechanism of heart injury among patients infected with SARS-CoV-2. Cardiovasc Res 2020; cvaa078.
23. Patel VB, Zhong J-C, Grant MB, et al. Role of the ACE2/Angiotensin 1-7 Axis of the Renin-Angiotensin System in Heart Failure. Circ Res 2016; 118: 1313–1326.
24. Vaduganathan M, Vardeny O, Michel T, et al. Renin–Angiotensin–Aldosterone System Inhibitors in Patients with Covid-19. N Engl J Med 2020; NEJMsr2005760.
25. Oudit GY, Kassiri Z, Jiang C, et al. SARS-coronavirus modulation of myocardial ACE2 expression and inflammation in patients with SARS. Eur J Clin Invest 2009; 39: 618–625.
26. Xu X, Chen P, Wang J, et al. Evolution of the novel coronavirus from the ongoing Wuhan outbreak and modeling of its spike protein for risk of human transmission. Sci China Life Sci 2020; 63: 457–460.
27. Zhu N, Zhang D, Wang W, et al. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N Engl J Med 2020; 382: 727–733.
28. Inciardi RM, Lupi L, Zaccone G, et al. Cardiac Involvement in a Patient With Coronavirus Disease 2019 (COVID-19). JAMA Cardiol. Epub ahead of print 27 March 2020. DOI: 10.1001/jamacardio.2020.1096.
29. Zeng JH, Liu Y-X, Yuan J, et al. First Case of COVID-19 Infection with Fulminant Myocarditis Complication: Case Report and Insights. Preprint, LIFE SCIENCES. Epub ahead of print 11 March 2020. DOI: 10.20944/preprints202003.0180.v1.
30. Hu H, Ma F, Wei X, et al. Coronavirus fulminant myocarditis treated with glucocorticoid and human immunoglobulin. Eur Heart J 2020; ehaa190.
31. Xu Z, Shi L, Wang Y, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med 2020; 8: 420–422.
32. Hamming I, Timens W, Bulthuis MLC, et al. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol 2004; 203: 631–637.
33. Tikellis C, Bernardi S, Burns WC. Angiotensin-converting enzyme 2 is a key modulator of the renin-angiotensin system in cardiovascular and renal disease. Curr Opin Nephrol Hypertens 2011; 20: 62–68.
34. Kuster GM, Pfister O, Burkard T, et al. SARS-CoV2: should inhibitors of the renin–angiotensin system be withdrawn in patients with COVID-19? Eur Heart J 2020; ehaa235.
35. Zhang H, Penninger JM, Li Y, et al. Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive Care Med 2020; 46: 586–590.
36. Guo J, Huang Z, Lin L, et al. Coronavirus Disease 2019 (COVID‐19) and Cardiovascular Disease: A Viewpoint on the Potential Influence of Angiotensin‐Converting Enzyme Inhibitors/Angiotensin Receptor Blockers on Onset and Severity of Severe Acute Respiratory Syndrome Coronavirus 2 Infection. J Am Heart Assoc; 9. Epub ahead of print 9 April 2020. DOI: 10.1161/JAHA.120.016219.
37. Yin S, Huang M, Li D, et al. Difference of coagulation features between severe pneumonia induced by SARS-CoV2 and non-SARS-CoV2. J Thromb Thrombolysis. Epub ahead of print 3 April 2020. DOI: 10.1007/s11239-020-02105-8.
38. Chong PY, Chui P, Ling AE, et al. Analysis of deaths during the severe acute respiratory syndrome (SARS) epidemic in Singapore: challenges in determining a SARS diagnosis. Arch Pathol Lab Med 2004; 128: 195–204.
39. Danzi GB, Loffi M, Galeazzi G, et al. Acute pulmonary embolism and COVID-19 pneumonia: a random association? Eur Heart J 2020; ehaa254.
40. Tang N, Li D, Wang X, et al. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost JTH 2020; 18: 844–847.
41. Idell S. Coagulation, fibrinolysis, and fibrin deposition in acute lung injury. Crit Care Med 2003; 31: S213-220.
42. Chang L-Y, Lu C-Y, Shao P-L, et al. Viral infections associated with Kawasaki disease. J Formos Med Assoc Taiwan Yi Zhi 2014; 113: 148–154.
43. Shirato K, Imada Y, Kawase M, et al. Possible involvement of infection with human coronavirus 229E, but not NL63, in Kawasaki disease. J Med Virol 2014; 86: 2146–2153.
44. Giray T, Biçer S, Küçük Ö, et al. Four cases with Kawasaki disease and viral infection: aetiology or association. Infez Med 2016; 24: 340–344.
45. Ding Y, Wang H, Shen H, et al. The clinical pathology of severe acute respiratory syndrome (SARS): a report from China. J Pathol 2003; 200: 282–289.
46. Chen, Yun-dai, Li, Yu-zhen, Liu, Xiu-hua, et al. Potential pathophysiological mechanisms underlying COVID-19-induced myocardial injury. Chin J Pathophysiol 2020; 36: 573–576.
47. Zheng Y-Y, Ma Y-T, Zhang J-Y, et al. COVID-19 and the cardiovascular system. Nat Rev Cardiol. Epub ahead of print 5 March 2020. DOI: 10.1038/s41569-020-0360-5.
48. Pan X, Xu D, Zhang H, et al. Identification of a potential mechanism of acute kidney injury during the COVID-19 outbreak: a study based on single-cell transcriptome analysis. Intensive Care Med. Epub ahead of print 31 March 2020. DOI: 10.1007/s00134-020-06026-1.
49. Madjid M, Miller CC, Zarubaev VV, et al. Influenza epidemics and acute respiratory disease activity are associated with a surge in autopsy-confirmed coronary heart disease death: results from 8 years of autopsies in 34 892 subjects. Eur Heart J 2007; 28: 1205–1210.
50. Nguyen JL, Yang W, Ito K, et al. Seasonal Influenza Infections and Cardiovascular Disease Mortality. JAMA Cardiol 2016; 1: 274.
51. Kwong JC, Schwartz KL, Campitelli MA, et al. Acute Myocardial Infarction after Laboratory-Confirmed Influenza Infection. N Engl J Med 2018; 378: 345–353.
52. Smeeth L, Thomas SL, Hall AJ, et al. Risk of Myocardial Infarction and Stroke after Acute Infection or Vaccination. N Engl J Med 2004; 351: 2611–2618.
53. Thygesen K, Alpert JS, Jaffe AS, et al. Fourth universal definition of myocardial infarction (2018). Eur Heart J 2019; 40: 237–269.
54. Bonow RO, Fonarow GC, O’Gara PT, et al. Association of Coronavirus Disease 2019 (COVID-19) With Myocardial Injury and Mortality. JAMA Cardiol. Epub ahead of print 27 March 2020. DOI: 10.1001/jamacardio.2020.1105.
55. Peiris J, Chu C, Cheng V, et al. Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: a prospective study. The Lancet 2003; 361: 1767–1772.
56. Xiong T-Y, Redwood S, Prendergast B, et al. Coronaviruses and the cardiovascular system: acute and long-term implications. Eur Heart J 2020; ehaa231.
57. Peiró C, Moncada S. Substituting Angiotensin-(1-7) to Prevent Lung Damage in SARSCoV2 Infection? Circulation 2020; CIRCULATIONAHA.120.047297.
58. Stanciu AE. Cytokines in heart failure. In: Advances in Clinical Chemistry. Elsevier, pp. 63–113.
59. Kofler S, Nickel T, Weis M. Role of cytokines in cardiovascular diseases: a focus on endothelial responses to inflammation. Clin Sci Lond Engl 1979 2005; 108: 205–213.
60. Mirzaei H, Ferns GA, Avan A, et al. Cytokines and MicroRNA in Coronary Artery Disease. In: Advances in Clinical Chemistry. Elsevier, pp. 47–70.
61. Teijaro JR, Walsh KB, Cahalan S, et al. Endothelial cells are central orchestrators of cytokine amplification during influenza virus infection. Cell 2011; 146: 980–991.
62. Cao B, Wang Y, Wen D, et al. A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19. N Engl J Med 2020; NEJMoa2001282.
63. Conti P, Gallenga CE, Tetè G, et al. How to reduce the likelihood of coronavirus-19 (CoV-19 or SARS-CoV-2) infection and lung inflammation mediated by IL-1. J Biol Regul Homeost Agents; 34. Epub ahead of print 31 2020. DOI: 10.23812/Editorial-Conti-2.
64. Zhang C, Wu Z, Li J-W, et al. The cytokine release syndrome (CRS) of severe COVID-19 and Interleukin-6 receptor (IL-6R) antagonist Tocilizumab may be the key to reduce the mortality. Int J Antimicrob Agents 2020; 105954.
65. Gaertner F, Massberg S. Blood coagulation in immunothrombosis-At the frontline of intravascular immunity. Semin Immunol 2016; 28: 561–569.
66. Thachil J. The versatile heparin in COVID-19. J Thromb Haemost. Epub ahead of print 2 April 2020. DOI: 10.1111/jth.14821.
67. Young E. The anti-inflammatory effects of heparin and related compounds. Thromb Res 2008; 122: 743–752.
68. Li J-P, Vlodavsky I. Heparin, heparan sulfate and heparanase in inflammatory reactions. Thromb Haemost 2009; 102: 823–828.
69. Esmon CT. Targeting factor Xa and thrombin: impact on coagulation and beyond. Thromb Haemost 2014; 111: 625–633.
70. Poterucha TJ, Libby P, Goldhaber SZ. More than an anticoagulant: Do heparins have direct anti-inflammatory effects? Thromb Haemost 2017; 117: 437–444.
71. Mousavi S, Moradi M, Khorshidahmad T, et al. Anti-Inflammatory Effects of Heparin and Its Derivatives: A Systematic Review. Adv Pharmacol Sci 2015; 2015: 507151.

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More information: Lucio Verdoni et al, An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study, The Lancet (2020). DOI: 10.1016/S0140-6736(20)31103-X